After HIV/AIDS, tuberculosis (TB) remains the second leading cause of death due to an infectious disease globally. Retrospective studies from many countries, including South Africa, have consistently reported that in addition to having a higher burden of TB disease, patients with problem alcohol use have worse TB treatment outcomes, including delayed culture conversion and higher rates of treatment failure, relapse, and death, compared to patients who do not consume alcohol. An estimated 10% of TB deaths are attributable to problematic alcohol use globally. Although one causal pathway to worse TB outcomes is through poor treatment adherence, observational studies and animals models suggest that the relationship between alcohol use and TB treatment outcomes persists after adjustment for suboptimal adherence. One potential biological mechanism is through alcohol's impact on the pharmacokinetics (PK) and pharmacodynamics (PD) of TB drugs. Problem alcohol use may lead to poorer absorption and/or accelerated metabolism of TB drugs, thereby increasing the risk of suboptimal sterilization. There is an urgent need to identify modifiable factors that contribute to poor TB treatment response, and understanding drivers of poor treatment response, both at the individual and population level, is essential for TB control. Investigators at Boston Medical Center (BMC), Boston University School of Medicine (BUSM), the South African Medical Research Council (MRC), and the University of Cape Town (UCT) propose to conduct the first prospective study to attempt to clarify the causal mechanisms underlying the deleterious effects of problem alcohol use on TB treatment outcomes. We plan to recruit 438 culture positive, pulmonary TB patients in Worcester, South Africa, an area highly endemic for both TB and problem alcohol use. The specific aims of this study are: 1) examine the associations between problem alcohol use and TB treatment outcomes, and (ii) demonstrate that these associations persist independent of adherence to TB treatment, and 2) to evaluate the effect of problematic alcohol use on the PK/PD of TB drugs. Our multidisciplinary approach will provide the best evidence to date addressing the complex interactions between TB and alcoholism and inform management strategies for countries facing these two epidemics.